Triggering TLR3 pathway promotes tumor growth and cisplatin resistance in head and neck cancer cells
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Hui-Ching Chuang1, Ming-Huei Chou2, Chih-Yen Chien1
1Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Abstract:
Over the last decades, significant advances in targeted therapies have helped provide more effective treatment for head and neck cancer patients. However, chemo-resistance to cisplatin significantly contributes to treatment failure in the clinical management of patients. In response to chemotherapeutic agents, certain molecules inside the cell are released or secreted from damaged or dead/dying cells, named damage-associated molecular patterns (DAMPs), thereby initiating an immune response through interaction with pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs). In present study, we investigated the link between cisplatin-induced DAMPs and TLR3 signaling. We found that cisplatin could be a potential activator of TLR3 and cisplatin treatment results in activation of PRRs' signaling and down-stream associated cytokine/chemokine, IFNβ, and CCL5 in TLR3High OC2 cells, but not in TLR3Low FaDu cells. Furthermore, knockdown of the TLR3 gene attenuates the expression of IFNβ and CCL5 mRNA and enhances the cytotoxicity of cisplatin in TLR3High OC2 cells. To determine whether TLR3 status affects the stress response of OC2 cells to cisplatin, we generated TLR3 knockdown OC2 cells (psi-TLR3 cells) with a psiRNA-hTLR3 plasmid containing shRNA to TLR3 and control OC2 cells (psi-NT cells) expressing non-silencing shRNA. OC2 cells were more sensitive to cisplatin treatment after TLR3 knockdown. In our animal model, OC2 psi-NT cells were more tumorigenic than were OC2 psi-TLR3 cells. Together, our in vitro and in vivo data imply TLR3 may contribute to tumor development and protect cisplatin-induced DNA damage response leading to cisplatin resistance in head and neck cancer cells.
Insights
Cisplatin resistance in head and neck cancer is linked to Toll-like receptor 3 (TLR3). Lowering TLR3 levels in cancer cells increases cisplatin sensitivity and reduces tumor growth, suggesting TLR3 inhibition as a potential therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Targeted therapies have improved head and neck cancer treatment, but cisplatin chemo-resistance remains a significant challenge.
- Chemotherapy can trigger the release of damage-associated molecular patterns (DAMPs), initiating immune responses via pattern recognition receptors (PRRs) like Toll-like receptors (TLRs).
- The specific role of TLR3 in cisplatin resistance in head and neck cancer is not fully understood.
Purpose of the Study:
- To investigate the association between cisplatin-induced DAMPs and TLR3 signaling in head and neck cancer.
- To determine the impact of TLR3 expression levels on cellular response to cisplatin treatment.
- To evaluate the therapeutic potential of targeting TLR3 in head and neck cancer models.
Main Methods:
- Investigated cisplatin-induced DAMPs and TLR3 signaling in TLR3-high (OC2) and TLR3-low (FaDu) head and neck cancer cell lines.
- Analyzed the expression of PRRs, IFNβ, and CCL5 following cisplatin treatment.
- Utilized TLR3 gene knockdown (psi-TLR3 cells) and control (psi-NT cells) in vitro and in vivo (animal models) to assess cisplatin sensitivity and tumorigenicity.
Main Results:
- Cisplatin activated TLR3 signaling, leading to increased IFNβ and CCL5 expression in TLR3High OC2 cells but not in TLR3Low FaDu cells.
- Knockdown of TLR3 in OC2 cells attenuated IFNβ and CCL5 mRNA expression and enhanced cisplatin-induced cytotoxicity.
- TLR3 knockdown OC2 cells exhibited reduced sensitivity to cisplatin and decreased tumorigenicity in vivo compared to control cells.
Conclusions:
- TLR3 activation by cisplatin may contribute to chemo-resistance in head and neck cancer.
- TLR3 signaling appears to protect cancer cells from cisplatin-induced DNA damage.
- Targeting TLR3 could represent a novel strategy to overcome cisplatin resistance and improve treatment outcomes in head and neck cancer.
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